Neurospora from natural populations: Population genomics insights into the Life history of a model microbial Eukaryote

The ascomycete filamentous fungus Neurospora crassa played a historic role in experimental biology and became a model system for genetic research. Stimulated by a systematic effort to collect wild strains initiated by Stanford geneticist David Perkins, the genus Neurospora has also become a basic model for the study of evolutionary processes, speciation, and population biology. In this chapter, we will first trace the history that brought Neurospora into the era of population genomics. We will then cover the major contributions of population genomic investigations using Neurospora to our understanding of microbial biogeography and speciation, and review recent work using population genomics and genome-wide association mapping that illustrates the unique potential of Neurospora as a model for identifying the genetic basis of (potentially adaptive) phenotypes in filamentous fungi. The advent of population genomics has contributed to firmly establish Neurospora as a complete model system and we hope our review will entice biologists to include Neurospora in their research

Stringy Stability of Charged Dilaton Black Holes with Flat Event Horizon

Electrically charged black holes with flat event horizon in anti-de Sitter space have received much attention due to various applications in Anti-de Sitter/Conformal Field Theory (AdS/CFT) correspondence, from modeling the behavior of quark-gluon plasma to superconductor. Crucial to the physics on the dual field theory is the fact that when embedded in string theory, black holes in the bulk may become vulnerable to instability caused by brane pair-production. Since dilaton arises naturally in the context of string theory, we study the effect of coupling dilaton to Maxwell field on the stability of flat charged AdS black holes. In particular, we study the stability of Gao-Zhang black holes, which are locally asymptotically anti-de Sitter. We find that for dilaton coupling parameter $\alpha$ > 1, flat black holes are stable against brane pair production, however for 0 < $\alpha$ < 1, the black holes eventually become unstable as the amount of electrical charges is increased. Such instability however, behaves somewhat differently from that of flat Reissner-Nordstr\"om black holes. In addition, we prove that the Seiberg-Witten action of charged dilaton AdS black hole of Gao-Zhang type with flat event horizon (at least in 5-dimension) is always logarithmically divergent at infinity for finite values of $\alpha$, and is finite and positive in the case $\alpha$ tends to infinity . We also comment on the robustness of our result for other charged dilaton black holes that are not of Gao-Zhang type.Comment: Fixed some confusions regarding whether part of the discussions concern electrically charged hole or magnetically charged one. No changes to the result

Perspectives of San Juan healthcare practitioners on the detection deficit in oral premalignant and early cancers in Puerto Rico: a qualitative research study

<p>Abstract</p> <p>Background</p> <p>In Puerto Rico, relative to the United States, a disparity exists in detecting oral precancers and early cancers. To identify factors leading to the deficit in early detection, we obtained the perspectives of San Juan healthcare practitioners whose practice could be involved in the detection of such oral lesions.</p> <p>Methods</p> <p>Key informant (KI) interviews were conducted with ten clinicians practicing in or around San Juan, Puerto Rico. We then triangulated our KI interview findings with other data sources, including recent literature on oral cancer detection from various geographic areas, current curricula at the University of Puerto Rico Schools of Medicine and Dental Medicine, as well as local health insurance regulations.</p> <p>Results</p> <p>Key informant-identified factors that likely contribute to the detection deficit include: many practitioners are deficient in knowledge regarding oral cancer and precancer; oral cancer screening examinations are limited regarding which patients receive them and the elements included. In Puerto Rico, specialists generally perform oral biopsies, and patient referral can be delayed by various factors, including government-subsidized health insurance, often referred to as Reforma. Reforma-based issues include often inadequate clinician knowledge regarding Reforma requirements/provisions, diagnostic delays related to Reforma bureaucracy, and among primary physicians, a perceived financial disincentive in referring Reforma patients.</p> <p>Conclusions</p> <p>Addressing these issues may be useful in reducing the deficit in detecting oral precancers and early oral cancer in Puerto Rico.</p

Temporal and Tissue Specific Regulation of RP-Associated Splicing Factor Genes PRPF3, PRPF31 and PRPC8—Implications in the Pathogenesis of RP

Genetic mutations in several ubiquitously expressed RNA splicing genes such as PRPF3, PRP31 and PRPC8, have been found to cause retina-specific diseases in humans. To understand this intriguing phenomenon, most studies have been focused on testing two major hypotheses. One hypothesis assumes that these mutations interrupt retina-specific interactions that are important for RNA splicing, implying that there are specific components in the retina interacting with these splicing factors. The second hypothesis suggests that these mutations have only a mild effect on the protein function and thus affect only the metabolically highly active cells such as retinal photoreceptors.We examined the second hypothesis using the PRPF3 gene as an example. We analyzed the spatial and temporal expression of the PRPF3 gene in mice and found that it is highly expressed in retinal cells relative to other tissues and its expression is developmentally regulated. In addition, we also found that PRP31 and PRPC8 as well as snRNAs are highly expressed in retinal cells.Our data suggest that the retina requires a relatively high level of RNA splicing activity for optimal tissue-specific physiological function. Because the RP18 mutation has neither a debilitating nor acute effect on protein function, we suggest that retinal degeneration is the accumulative effect of decades of suboptimal RNA splicing due to the mildly impaired protein

C. albicans Colonization of Human Mucosal Surfaces

Background: Candida albicans is a low level commensal organism in normal human populations with the continuous potential to expand and cause a spectrum of clinical conditions. Methodology/Principal Findings: Using ex vivo human organ cultures and populations of primary human cells, we have developed several related experimental systems to examine early-stage interactions between C. albicans and mucosal surfaces. Experiments have been conducted both with exogenously added C. albicans and with overtly normal human mucosal surfaces supporting pre-existing infections with natural isolates of Candida. Under different culture conditions, we have demonstrated the formation of C. albicans colonies on human target cells and filament formation, equivalent to tissue invasion. Conclusions/Significance: These organ culture systems provide a valuable new resource to examine the molecular and cellular basis for Candida colonization of human mucosal surfaces

Absence of Positive Selection on Centromeric Histones in Tetrahymena Suggests Unsuppressed Centromere-Drive in Lineages Lacking Male Meiosis

Centromere-drive is a process where centromeres compete for transmission through asymmetric "female" meiosis for inclusion into the oocyte. In symmetric "male" meiosis, all meiotic products form viable germ cells. Therefore, the primary incentive for centromere-drive, a potential transmission bias, is believed to be missing from male meiosis. In this article, we consider whether male meiosis also bears the primary cost of centromere-drive. Because different taxa carry out different combinations of meiotic programs (symmetric + asymmetric, symmetric only, asymmetric only), it is possible to consider the evolutionary consequences of centromere-drive in the context of these differing systems. Groups with both types of meiosis have large, rapidly evolving centromeric regions, and their centromeric histones (CenH3s) have been shown to evolve under positive selection, suggesting roles as suppressors of centromere-drive. In contrast, taxa with only symmetric male meiosis have shown no evidence of positive selection in their centromeric histones. In this article, we present the first evolutionary analysis of centromeric histones in ciliated protozoans, a group that only undergoes asymmetric "female" meiosis. We find no evidence of positive selection acting on CNA1, the CenH3 of Tetrahymena species. Cytological observations of a panel of Tetrahymena species are consistent with dynamic karyotype evolution in this lineage. Our findings suggest that defects in male meiosis, and not mitosis or female meiosis, are the primary selective force behind centromere-drive suppression. Our study raises the possibility that taxa like ciliates, with only female meiosis, may therefore undergo unsuppressed centromere drive

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care